SUMMARY Skeletal muscle regeneration requiresactivationand proliferationofa resident populationof stemcells known assatellitecells.Satellitecellsarenotonlyrequiredformuscleregenerationafterinjurybutarealsothoughtto contributetoongoingmaintenanceofmusclemass.Unfortunately,thenumberandactivityoftheseprogenitors declines with aging and muscular dystrophy. Therefore, pharmacologic strategies to promote expansion of myogenicsatellitecellscouldpotentiallybeusedtoimprovemuscleregenerationandpreservemusclefunction in individuals with muscle disease or individuals of advanced age. Signaling through the cAMP pathway stimulates myogenic progenitor cell proliferation during embryonic development and is sufficient to stimulate proliferationofthesecellsinvitro.Thispathwayisalsoactivatedduringregenerationinadultmice.However,it is unknown whether cAMP signaling in myogenicprogenitor cells in responseto injury is sufficientto enhance proliferation in vivo. We previously showed that the cAMP-responsive transcription factor CREB isactivated in areasofproliferation after acute muscle injury inmice and that mice expressing an activated mutant of CREB haveenhancedmyoblastproliferationafterinjury.Thisprojectemploysbiochemicalandchemical-genetictools todeterminewhetherchemical-geneticelevationandgeneticregulationofcAMPsignalingspecificallyinsatellite cells alters proliferation and muscle regeneration in vivo through regulation of CREB/CRTC transcriptional complexes. We will interrogate the regulationand function ofcAMP-regulated CREB co-activators (CRTCs) in satellitecellproliferationanduseunbiasedtranscriptomicapproachestoidentifyCREB/CRTCtargetgenesthat contribute to the cAMP-driven proliferative response. We will undertake mechanistic studies to characterize molecular regulation of CRTCs and the mechanism of CRTC recruitment to cAMP-regulated genes in proliferating satellite cells. Results of this project will yield insights into fundamental mechanisms that drive satellitecellproliferationandexpansion.Thelong-termgoalistoidentifynewpharmacologictargetstoimprove muscleregenerationandfunctioninpatientswithmusclediseaseandage-relatedsarcopenia.